The goal of the proposed work is to discover and begin development of novel therapeutics for life-threatening fungal infections. In recent years, there has been a marked increase in fungal infections as a result of the growing number of immunosuppressed and immunocompromised individuals, such as individuals with AIDS, transplant recipients, and chemotherapy or radiotherapy patients. Presently, very few antifungal therapeutics are approved for human use, and those that are approved act against a limited set of biochemical targets. What is more, infections caused by resistant fungi are becoming more common. With SBIR Phase I funding an in vitro drug discovery system for identifying translation- targeted antifungals was developed and validated. In Phase II, these in vitro assays will be used for a large-scale screening program intended to identify compounds with antifungal activity. Candidates identified by in vitro screening will be tested against Aspergillus, Candida, and Cryptococcus in animal models of fungal infection. A medicinal chemistry program will be used interactively with the screening program to generate derivatives of lead compounds having an improved therapeutic profile. Lead compounds of sufficient promise that are discovered in Phase II will be developed further through preclinical an clinical trials during Phase III. PROPOSED COMMERCIAL APPLICATION: This research will be used to identify a new class of antifungal therapeutics targeted against protein translation. In addition to being potential therapeutics, some compounds identified by this screen may be useful as probes in basic research on translation, or as antifungal agents in agricultural or industrial contexts.